The complement system is an essential part of the body's natural defence mechanism against foreign invasion and is also involved in the inflammatory process. More than 30 proteins in serum and at the cell surface are involved in complement system function and regulation. Recently it has become apparent that, as well as the ˜35 known components of the complement system which may be associated with both beneficial and pathological processes, the complement system itself interacts with at least 85 biological pathways with functions as diverse as angiogenesis, platelet activation, glucose metabolism and spermatogenesis [1].
The complement system is activated by the presence of foreign antigens. Three activation pathways exist: (1) the classical pathway which is activated by IgM and IgG complexes or by recognition of carbohydrates; (2) the alternative pathway which is activated by non-self surfaces (lacking specific regulatory molecules) and by bacterial endotoxins; and (3) the lectin pathway which is activated by binding of manna-binding lectin (MBL) to mannose residues on the surface of a pathogen. The three pathways comprise parallel cascades of events that result in the production of complement activation through the formation of similar C3 and C5 convertases on cell surfaces resulting in the release of acute mediators of inflammation (C3a and C5a) and formation of the membrane attack complex (MAC). The parallel cascades involved in the classical and alternative pathways are shown in FIG. 1.
Complement can be activated inappropriately under certain circumstances leading to undesirable local tissue destruction. Inappropriate complement activation has been shown to play a role in a wide variety of diseases and disorders including acute pancreatitis, Alzheimer's disease, allergic encephalomyelitis, allotransplatation, asthma, adult respiratory distress syndrome, burn injuries, Crohn's disease, glomerulonephritis, haemolytic anaemia, haemodialysis, hereditary angioedema, ischaemia reperfusion injuries, multiple system organ failure, multiple sclerosis, myasthenia gravis, ischemic stroke, myocardial infarction, psoriasis, rheumatoid arthritis, septic shock, systemic lupus erythematosus, stroke, vascular leak syndrome, transplantation rejection and inappropriate immune response in cardiopulmonary bypass operations. Inappropriate activation of the complement system has thus been a target for therapeutic intervention for many years and numerous complement inhibitors targeting different parts of the complement cascade are under development for therapeutic use.
In ischemic stroke and myocardial infarction, the body recognises the dead tissue in the brain or heart as foreign and activates complement so causing further local damage. Similarly in cardiopulmonary bypass operations, the body recognises the plastic surfaces in the machine as foreign, activates complement and can result in vascular damage. In autoimmune diseases, the body may wrongly recognise itself as foreign and activate complement with local tissue damage (e.g. joint destruction in rheumatoid arthritis and muscle weakness in myasthenia gravis).
In the peripheral nervous system, several types of neuropathy are autoimmune in origin and circulating autoantibodies to myelin and Schwann cell antigens have been detected [2]. Complement is implicated as an effector in inflammatory demyelination observed in experimental allergic neuritis (EAN), a model for Guillain-Barre syndrome, an immune-mediated acquired human demyelinating neuropathy [3].
Peripheral nerve disorders can be chronic and come on very slowly over several months or years. An example of such an illness is chronic inflammatory demyelinating polyradiculoneuropathy, known as CIDP. Sometimes peripheral nerve disorders are acute and come on very rapidly over the course of a few days, for example post-infective demyelinating polyradiculoneuropathy, better known as Guillain-Barre Syndrome (GBS). CIDP was once known as ‘chronic GBS’ and is regarded as a related condition to GBS.
GBS is a rare condition (prevalence is 1-2 per 100,000 or ˜3,000 cases in the USA per year). About half the cases of GBS occur after a bacterial or viral infection. GBS is an autoimmune disorder in which the body produces antibodies that damage the myelin sheath that surrounds peripheral nerves. The myelin sheath is a fatty substance that surrounds axons, which increases the speed at which signals travel along the nerves.
Once these antibodies react with the antigen (the myelin sheath) the complement system is activated and C5 is produced. C5 breaks down to C5a and C5b which becomes C5b-9 (the membrane attack complex). C5a attracts white cells and C5b-9 opens blood vessels wall to allow white cell ingress into the tissues. Suitably stimulated white cells release destructive cytokines causing local damage to the nerves.
Clinically, GBS is characterised by weakness and numbness or tingling in the legs and arms, and possible loss of movement and feeling in the legs, arms, upper body, and face. The first symptoms of GBS are usually numbness or tingling (paresthesia) in the toes and fingers, with progressive weakness in the arms and legs over the next few days. Some patients experience paresthesia only in their toes and legs; others only experience symptoms on one side of the body.
The symptoms may stay in this phase, causing only mild difficulty in walking, requiring crutches or a walking stick. However, sometimes the illness progresses, leading to complete paralysis of the arms and legs. About one quarter of the time, the paralysis continues up the chest and freezes the breathing muscles, leaving the patient dependant on a ventilator. If the swallowing muscles are also affected, a feeding tube may be needed.
GBS is considered a medical emergency and most patients are admitted to intensive care soon after diagnosis. Though GBS can improve spontaneously, there are a number of treatments that facilitate recovery. Most patients with GBS and CIDP are treated with plasmapheresis (blood plasma exchange) or large doses of immunoglobulin. In extreme cases filtration of the CerebroSpinal Fluid has been used. Ventilation, plasmapheresis and immunoglobulin are extremely expensive.
There is thus a great need for agents that improve upon the currently available treatments for peripheral nerve disorders such as CIDP and GBS.